Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (K.M.B., J.E.M., X.W., L.M.A.), Environmental and Occupational Health Sciences Institute (L.M.A.), and Lipid Center (L.M.A.), Rutgers, The State University of New Jersey, Piscataway, New Jersey; Department of Pediatrics, Rutgers University Robert Wood Johnson Medical School, New Brunswick, New Jersey (F.A., P.Y.S.Y., M.M., N.M., A.M.V.); Hofstra Northwell School of Medicine, Cohen Children’s Medical Center of New York, New Hyde Park, New York (B.I.W.); and Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado (L.M.S.)

Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (K.M.B., J.E.M., X.W., L.M.A.), Environmental and Occupational Health Sciences Institute (L.M.A.), and Lipid Center (L.M.A.), Rutgers, The State University of New Jersey, Piscataway, New Jersey; Department of Pediatrics, Rutgers University Robert Wood Johnson Medical School, New Brunswick, New Jersey (F.A., P.Y.S.Y., M.M., N.M., A.M.V.); Hofstra Northwell School of Medicine, Cohen Children’s Medical Center of New York, New Hyde Park, New York (B.I.W.); and Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado (L.M.S.)

Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (K.M.B., J.E.M., X.W., L.M.A.), Environmental and Occupational Health Sciences Institute (L.M.A.), and Lipid Center (L.M.A.), Rutgers, The State University of New Jersey, Piscataway, New Jersey; Department of Pediatrics, Rutgers University Robert Wood Johnson Medical School, New Brunswick, New Jersey (F.A., P.Y.S.Y., M.M., N.M., A.M.V.); Hofstra Northwell School of Medicine, Cohen Children’s Medical Center of New York, New Hyde Park, New York (B.I.W.); and Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado (L.M.S.)

Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (K.M.B., J.E.M., X.W., L.M.A.), Environmental and Occupational Health Sciences Institute (L.M.A.), and Lipid Center (L.M.A.), Rutgers, The State University of New Jersey, Piscataway, New Jersey; Department of Pediatrics, Rutgers University Robert Wood Johnson Medical School, New Brunswick, New Jersey (F.A., P.Y.S.Y., M.M., N.M., A.M.V.); Hofstra Northwell School of Medicine, Cohen Children’s Medical Center of New York, New Hyde Park, New York (B.I.W.); and Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado (L.M.S.)

Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (K.M.B., J.E.M., X.W., L.M.A.), Environmental and Occupational Health Sciences Institute (L.M.A.), and Lipid Center (L.M.A.), Rutgers, The State University of New Jersey, Piscataway, New Jersey; Department of Pediatrics, Rutgers University Robert Wood Johnson Medical School, New Brunswick, New Jersey (F.A., P.Y.S.Y., M.M., N.M., A.M.V.); Hofstra Northwell School of Medicine, Cohen Children’s Medical Center of New York, New Hyde Park, New York (B.I.W.); and Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado (L.M.S.)

Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (K.M.B., J.E.M., X.W., L.M.A.), Environmental and Occupational Health Sciences Institute (L.M.A.), and Lipid Center (L.M.A.), Rutgers, The State University of New Jersey, Piscataway, New Jersey; Department of Pediatrics, Rutgers University Robert Wood Johnson Medical School, New Brunswick, New Jersey (F.A., P.Y.S.Y., M.M., N.M., A.M.V.); Hofstra Northwell School of Medicine, Cohen Children’s Medical Center of New York, New Hyde Park, New York (B.I.W.); and Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado (L.M.S.)

Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (K.M.B., J.E.M., X.W., L.M.A.), Environmental and Occupational Health Sciences Institute (L.M.A.), and Lipid Center (L.M.A.), Rutgers, The State University of New Jersey, Piscataway, New Jersey; Department of Pediatrics, Rutgers University Robert Wood Johnson Medical School, New Brunswick, New Jersey (F.A., P.Y.S.Y., M.M., N.M., A.M.V.); Hofstra Northwell School of Medicine, Cohen Children’s Medical Center of New York, New Hyde Park, New York (B.I.W.); and Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado (L.M.S.)

Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (K.M.B., J.E.M., X.W., L.M.A.), Environmental and Occupational Health Sciences Institute (L.M.A.), and Lipid Center (L.M.A.), Rutgers, The State University of New Jersey, Piscataway, New Jersey; Department of Pediatrics, Rutgers University Robert Wood Johnson Medical School, New Brunswick, New Jersey (F.A., P.Y.S.Y., M.M., N.M., A.M.V.); Hofstra Northwell School of Medicine, Cohen Children’s Medical Center of New York, New Hyde Park, New York (B.I.W.); and Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado (L.M.S.)

Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (K.M.B., J.E.M., X.W., L.M.A.), Environmental and Occupational Health Sciences Institute (L.M.A.), and Lipid Center (L.M.A.), Rutgers, The State University of New Jersey, Piscataway, New Jersey; Department of Pediatrics, Rutgers University Robert Wood Johnson Medical School, New Brunswick, New Jersey (F.A., P.Y.S.Y., M.M., N.M., A.M.V.); Hofstra Northwell School of Medicine, Cohen Children’s Medical Center of New York, New Hyde Park, New York (B.I.W.); and Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado (L.M.S.)

Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (K.M.B., J.E.M., X.W., L.M.A.), Environmental and Occupational Health Sciences Institute (L.M.A.), and Lipid Center (L.M.A.), Rutgers, The State University of New Jersey, Piscataway, New Jersey; Department of Pediatrics, Rutgers University Robert Wood Johnson Medical School, New Brunswick, New Jersey (F.A., P.Y.S.Y., M.M., N.M., A.M.V.); Hofstra Northwell School of Medicine, Cohen Children’s Medical Center of New York, New Hyde Park, New York (B.I.W.); and Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado (L.M.S.)

Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy (K.M.B., J.E.M., X.W., L.M.A.), Environmental and Occupational Health Sciences Institute (L.M.A.), and Lipid Center (L.M.A.), Rutgers, The State University of New Jersey, Piscataway, New Jersey; Department of Pediatrics, Rutgers University Robert Wood Johnson Medical School, New Brunswick, New Jersey (F.A., P.Y.S.Y., M.M., N.M., A.M.V.); Hofstra Northwell School of Medicine, Cohen Children’s Medical Center of New York, New Hyde Park, New York (B.I.W.); and Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado (L.M.S.)

Visual Overview

Abstract

The breast cancer resistance protein (BCRP/ABCG2) is a maternally-facing efflux transporter that regulates the placental disposition of chemicals. Transcription factors and gene variants are important regulatory factors that influence transporter expression. In this study, we sought to identify the genetic and transcriptional mechanisms underlying the interindividual expression of BCRP mRNA and protein across 137 term placentas from uncomplicated pregnancies. Placental expression of BCRP and regulatory transcription factor mRNAs was measured using multiplex-branched DNA analysis. BCRP expression and ABCG2 genotypes were determined using Western blot and Fluidigm Biomark genetic analysis, respectively. Placentas were obtained from a racially and ethnically diverse population, including Caucasian (33%), African American (14%), Asian (14%), Hispanic (15%), and mixed (16%) backgrounds, as well as unknown origins (7%). Between placentas, BCRP mRNA and protein varied up to 47-fold and 14-fold, respectively. In particular, BCRP mRNA correlated significantly with known transcription factor mRNAs, including nuclear factor erythroid 2-related factor 2 and aryl hydrocarbon receptor. Somewhat surprisingly, single-nucleotide polymorphisms (SNPs) in the ABCG2 noncoding regions were not associated with variation in placental BCRP mRNA or protein. Instead, the coding region polymorphism (C421A/Q141K) corresponded with 40%–50% lower BCRP protein in 421C/A and 421A/A placentas compared with wild types (421C/C). Although BCRP protein and mRNA expression weakly correlated (r = 0.25, P = 0.040), this relationship was absent in individuals expressing the C421A variant allele. Study results contribute to our understanding of the interindividual regulation of BCRP expression in term placentas and may help to identify infants at risk for increased fetal exposure to chemicals due to low expression of this efflux protein.

Footnotes

Received October 28, 2017.

Accepted January 25, 2018.

This work was supported by National Institutes of Health National Institute of Environmental Health Sciences [Grants ES020522, ES005022, and ES007148]. A portion of tissue samples was provided by the National Institutes of Health Placental Bank in University of California, San Francisco, supported by National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development [Grant HD055764]. K.M.B. was supported by predoctoral fellowships from the American Foundation for Pharmaceutical Education and Pharmaceutical Research and Manufacturers of America. J.E.M. was supported by predoctoral fellowships from the American Foundation for Pharmaceutical Education and the National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Development [Grant F31HD082965].